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Culprit in Grapefruit Juice Drug Interaction Identified

Over 15 years ago, researchers uncovered a dangerous interaction between grapefruit juice and certain medications when they gave volunteers grapefruit juice to mask the taste of a medication. Now, scientists have identified the ingredients responsible, which may enable manufacturers to create a grapefruit juice that doesn’t have the same effect.

After the discovery of the grapefruit juice effect, NIH-funded researchers identified
a prominent enzyme called CYP3A4 as the juice’s target. CYP3A4 is found in the
cells that line the small intestine and helps break down about half of all marketed
drugs. Grapefruit juice inhibits this enzyme, causing more of the drugs to enter
the blood stream and effectively resulting in doses that are too strong.

Researchers originally thought that compounds called flavonoids were responsible
because they’re present in high concentrations in grapefruit juice and were shown
to inhibit CYP3A4 in laboratory experiments. When purified flavonoids were tested
in humans, however, they didn’t show the same effect. Two of another class of
chemicals called furanocoumarins are abundant in grapefruit juice and also inhibited
CYP3A4 in laboratory tests. Human studies showed that while those two chemicals
do have an effect in the body, they don’t account for the full effect of the
juice.

A team of researchers funded by NIH and led by Paul B Watkins at the University
of North Carolina at Chapel School of Medicine used a method to remove nearly
all of the different types of furanocoumarins from grapefruit juice to test the
idea that furanocoumarins really are responsible for the grapefruit juice effect.
They compared the modified grapefruit juice with orange juice, which has little
effect on CYP3A4, and with unaltered grapefruit juice.

In the May issue of the American Journal of Clinical Nutrition, the
researchers report that removing furanocoumarins from grapefruit juice took away
its drug-altering effects. The scientists gave 18 healthy volunteers one of the
three juices along with 10 milligrams of felodipine, a blood-pressure drug known
to interact with grapefruit juice. Their blood was collected over 24 hours to
measure felodipine levels. In contrast to those who drank unaltered grapefruit
juice, the people who drank furanocoumarin-free grapefruit juice had blood levels
of felodipine similar to those who’d had the orange juice.

The food-grade methods the researchers used can potentially be used to make
furanocoumarin-free grapefruit juice commercially. Knowing the compounds responsible
for these drug interactions has other benefits, too. It can now help scientists
spot potential drug interactions in other foods. These compounds might even be
used in medications one day to enhance their effectiveness.